Neutrophil-lymphocyte ratio reflects tumor infiltrating lymphocytes, tumor associated macrophages and independently predicts poor outcome in breast cancers with neoadjuvant chemotherapy

doi:10.21203/rs.3.rs-3131045/v1

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Neutrophil-lymphocyte ratio reflects tumor infiltrating lymphocytes, tumor associated macrophages and independently predicts poor outcome in breast cancers with neoadjuvant chemotherapy

https://doi.org/10.21203/rs.3.rs-3131045/v1

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Introduction

The neutrophil-lymphocyte ratio (NLR) is a systemic reflection of cancer-associated inflammation and a prognostic marker for breast cancer. For the local tumor microenvironment, tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs) are also highly correlated with breast cancer survival. This study aims to explore the relationship between the circulating and local immune microenvironment, and to further delineate the prognostic role of NLR in breast cancer patients receiving neoadjuvant chemotherapy (NAC).

Methods

A cohort of breast cancer patients receiving NAC with subsequent was retrieved. Clinical data were reviewed. Histologic slides and CD8 immunohistochemistry from biopsy (pre-chemotherapy) and excision (post-chemotherapy) specimens were assessed for TILs and TAMs.

Results

Totally 146 patients were included. There was significant positive correlation between pre-chemotherapy and post-surgery NLR at a cutoff of 2.6 (median pre-chemotherapy NLR) (p<.001). NLR pre-chemotherapy was associated positively with necrosis on biopsy (p=.027) and excision (p=.021) and TAMs on excision (p=.049). NLR one-year post-surgery was associated with high tumor stage (p=.050) and low histologic grade (p=.008). TIL count was lower in NLR-high cases at nearly all time points, by histologic assessment and CD8 immunostaining (p<.050). In multivariate analysis, post-surgery NLR is an independent predictor for overall survival (OS) (HR=9.524, p<.001), breast cancer specific survival (BCSS) (HR=10.059, p=.001) and disease-free survival (DFS) (HR=2.824, p=.016).

Conclusion

The association between NLR with tumor necrosis, TAM and TIL illustrates an interaction between the circulating and local immune microenvironment. Late NLR is a strong indicator of outcome and may be useful for prognostication and disease monitoring.

Neutrophil-lymphocyte ratio

tumor infiltrating lymphocytes

tumor associated macrophages

breast cancer

neoadjuvant chemotherapy

The neutrophil-lymphocyte ratio (NLR) is a prognostic marker for human cancers including breast cancer (1). It is believed to reflect systemic changes induced by cancer-associated inflammation, from which it derives its prognostic association (2). As for the local tumor microenvironment, the major immune components consist of tumor infiltrating lymphocytes (TILs) and tumor associated macrophages (TAMs). TILs and TAMs are highly correlated with survival in breast cancer (3). Studies on colorectal cancers have demonstrated negative correlation between TILs and NLR (4, 5), but findings are not replicated in cohorts of breast and ovarian cancers (6–8). It is also uncertain whether NLR and TIL counts are closely related measures of the tumor microenvironment, or that they are distinct factors with independent prognostic values. In the current study of a cohort of breast cancer patients treated with NAC, NLRs at multiple time points were compared with immune cells, clinical and histologic prognostic variables and clinical outcomes. This study aims to explore the relationship between the circulating and local tumor microenvironment, and to further delineate the prognostic role of NLR in breast cancer.

A computerized search of the department pathology archives of the involved institutions from the year 2007 to 2018 was performed to identify breast biopsy and excision specimens from cases with NAC performed. Pathology reports and clinical case notes were reviewed for complete blood counts, demographic, staging, treatment, and outcome data. Lymphocyte and neutrophil counts at multiple time points, including pre-chemotherapy (within one month before initiation of chemotherapy), post-chemotherapy (within three months after completion of chemotherapy) and late post-surgery (at least one year after surgery), were retrieved for calculation of NLR, defined as the absolute neutrophil count divided by the absolute lymphocyte count. Hematoxylin and eosin (H&E) slides were reviewed for histopathologic parameters, including tumor grade (modified Bloom-Richardson), presence of necrosis, pathologic response post NAC, TILs and TAMs. CD8 (tumoral and stromal), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 immunohistochemistry (IHC) were performed on both pre-chemotherapy biopsy and post-chemotherapy excision specimens. Assessment of H&E and IHC were performed by two authors (SN and GT) and discrepancies were resolved by viewing the slides on a multiheaded microscope until a consensus was reached. This study was approved by the Joint Chinese University of Hong Kong - New Territories East Cluster clinical research ethics committee with waiver of requirement for written consent.

Statistical analysis

Statistical analysis was performed using SPSS (version 23.0; IBM, USA). The Pearson’s chi-squared test and student’s t-test were used for comparing histological parameters, demographical and clinical data with NLR. Kaplan-Meier survival curve was used to compare survival outcomes (disease free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)). The backward Wald method was used for multivariate analysis. A p value of < .05 was considered significant.

Totally 146 female breast cancer patients who received NAC were included, with a mean age of patient 51.3 (27–81) years. The average tumor size was 57.3 (10–180) mm. Thirty-four cases were clinically node negative (23.6%, n = 34/144). The majority of the tumors were histologically grade 3 (78.4%, n = 105/134). ER, PR and HER2 positivity were found in 67.9% (n = 89/131), 56.0% (n = 75/134) and 38.8% (n = 52/134) of cases respectively, with 31 HER2-positive, hormone receptor-negative and 16 triple negative cases. Ki-67 proliferation index was greater than 20% in 90.3% (n = 121/134) of cases. Thirty-four patients received anti-HER2 therapy in conjunction with NAC. Pathological complete response (pCR), partial response and no response (including those with disease progression) were seen in 20, 67 and 49 patients respectively. Distance metastases were detected in 12 cases prior to NAC and remained in 11 cases.

NLR data were available for 127 cases pre-chemotherapy, 134 cases post-chemotherapy and 129 cases late post-surgery. The median (and interquartile range of) NLR at pre-chemotherapy, post-chemotherapy and late post-surgery were 2.60 (1.87–3.41), 3.11 (2.00-4.85) and 2.60 (1.78–4.25) respectively. Using the median NLR value at pre-chemotherapy (i.e. 2.6) as cutoff, significant positive correlation was found between pre-chemotherapy and post-surgery NLR (p < .001). NLR at post-chemotherapy only showed marginal correlation with NLRs at other time points (p = .096, p = .080). In the 107 cases with complete NLR data at all three time points, 13 and 33 cases were constantly NLR-low or NLR-high. The most common pattern among the remaining cases (n = 25/61, 41%) was NLR-high at post-chemotherapy and NLR-low at other time points.

Comparing with clinicopathological parameters, NLR pre-chemotherapy was associated positively with the presence of necrosis at both biopsy (p = .027) and surgical excision (p = .021) and the presence of macrophages at excision (p = .049) (Fig. 1). For NLR post-chemotherapy, it was associated negatively with anti-HER2 therapy (p = .032) and tumor grade at biopsy (p = .047), but positively with PR positivity at biopsy (p = .039) and the presence of necrosis at excision (p = .050). NLR post-surgery was positively associated with high tumor stage (size) (p = 0.050) and low histological grade (p = 0.008) at baseline pre-chemotherapy. Age, pre-treatment nodal and metastasis staging, biomarker expression, post-treatment staging as well as treatment response did not demonstrate significant associations with NLR (Table 1).

Table 1

Clinico-pathological association with neutrophil-lymphocyte ratio (NLR)
		Pre-chemotherapy NLR (within one month before initiation of chemotherapy)			Post-chemotherapy NLR (within three months after completion of chemotherapy)			Late post-surgery NLR (at least one year after surgery)
		Low*	High	p-value	Low	High	p-value	Low	High	p-value
Post chemotherapy	Low	26	14	0.08
	High	39	42
Late post-surgery	Low	39	16	< .001	23	33	0.096
	High	18	40		16	45
Clinical
Age	<=50	31	36	0.174	27	42	0.526	34	35	0.991
	> 50	35	25		22	43		30	31
Size	<=50	38	26	0.11	29	41	0.177	38	29	0.050
	> 50	28	34		19	44		24	37
Nodal stage	0	15	13	0.897	14	19	0.619	14	13	0.86
	1/2	46	41		31	58		39	47
	3	5	6		3	8		8	6
Distant metastasis	Absent	35	24	1	29	38	0.503	31	32	0.523
	Present	5	3		5	4		4	7
Anti-HER2 therapy	Absent	43	44	0.256	30	64	0.032	44	46	0.461
	Present	19	12		17	15		17	13
Biopsy
Grade	1/2	12	14	0.485	6	22	0.047	7	19	0.008
	3	48	41		40	55		52	40
Necrosis	Absent	41	27	0.027	28	49	0.876	36	38	0.614
	Present	18	28		17	28		23	20
ER	Negative	17	17	0.839	17	22	0.424	20	13	0.216
	Positive	41	37		28	53		38	45
PR	Negative	26	22	0.850	26	28	0.039	28	21	0.262
	Positive	34	33		20	49		31	38
HER2	Negative	35	36	0.584	26	50	0.353	36	37	0.850
	Positive	24	20		20	27		23	22
Ki67	Low	5	6	0.639	4	9	0.765	3	7	0.186
	High	55	49		42	68		56	52
Excision
Grade	1	6	11	0.087	3	14	0.162	6	11	0.626
	2	24	25		18	34		25	25
	3	20	13		14	22		16	19
Necrosis	No	47	32	0.021	33	54	0.05	41	44	0.887
	Yes	7	15		3	17		10	10
	Total	49	47		35	68		52	53
Macrophage	No	43	30	0.049	27	50	0.457	36	41	0.555
	Yes	14	22		11	28		21	19
ER	Negative	4	10	0.088	7	10	0.581	7	8	1
	Positive	42	35		27	54		38	43
PR	Negative	28	28	0.559	21	39	1	31	26	0.175
	Positive	27	21		17	34		20	30
HER2	Negative	37	33	0.890	24	52	0.445	34	40	0.695
	Positive	18	17		14	22		17	17
Ki67	Low	31	34	0.317	19	50	0.079	28	38	0.324
	High	22	16		18	23		21	19
Tumor stage (ypT)	0	11	10	0.847	10	11	0.735	11	10	0.128
	1	26	25		16	38		28	25
	2	21	19		15	28		21	22
	3	5	1		4	3		2	4
	4	3	6		4	5		1	5
Nodal stage (ypN)	0	26	25	0.869	23	31	0.274	26	22	0.139
	1	21	19		15	29		22	21
	2	16	11		8	19		12	16
	3	3	6		3	6		3	7
Distant metastasis	Absent	61	59	0.442	44	81	0.287	60	59	0.325
	Present	5	2		5	4		3	7
Treatment response	Complete	8	8	0.496	8	8	0.655	8	8	0.324
	Partial	34	35		24	49		37	33
	None	24	18		17	28		17	25
pCR	No	58	53	0.867	41	77	0.238	55	58	0.922
	Yes	8	8		8	7		8	8
* A cutoff of 2.6 (median at pre-chemotherapy) for high/low NLR was used ** ER – estrogen receptor, HER2 – human epidermal growth factor receptor 2, PR – progesterone receptor

Comparing TILs between NLR-high and NLR-low cases, TIL count was lower in NLR-high cases at nearly all time points and by both histologic assessment and CD8 immunostaining (Table 2). The exception was that higher CD8 + stromal TILs on biopsy in post-chemotherapy NLR-high cases, but statistical significance was not reached (p = .447). Statistically significant correlation was seen comparing TILs on biopsy and late post-surgery NLR (p = .040), with trends for both biopsy and excision with post-chemotherapy NLR (p = .089 and p = .082), and excision with pre-chemotherapy NLR (p = .077). Stromal and tumoral CD8-positive TIL counts were significantly lower for pre-chemotherapy NLR-high cases (p = .049 and p = .010), and a trend was observed for lower tumoral CD8-positive TIL count and post-chemotherapy NLR-high cases (p = .064) (Fig. 2).

Table 2

Comparison between neutrophil-lymphocyte ratio (NLR) and tumor infiltrating lymphocytes (TILs)
		Pre-chemotherapy NLR (within one month before initiation of chemotherapy)		Post-chemotherapy NLR (within three months after completion of chemotherapy)		Late post-surgery NLR (at least one year after surgery)
		Low	High	Low	High	Low	High
Biopsy
	Case number	61	54	44	78	58	57
Stromal TIL	Median	30%	10%	20%	10%	30%	15%
	IQR	10–50%	5–30%	7–50%	2–35%	5–60%	3–30%
	p-value		.366		.089		.040
Stromal CD8 + TIL*	Median	93.9	45.0	47.8	58.4	64.9	52.8
	IQR	18.2-271.2	6.7-134.3	17.9-210.2	9.0-185.0	18.2-163.1	8.1-210.6
	p-value		.049		.447		.761
Tumoral CD8 + TIL*	Median	91.1	25.4	65.8	30.7	86.6	38.1
	IQR	10.3-235.5	3.0-76.8	16.4-217.2	4.1–30.7	12.2-136.1	5.9-165.3
	p-value		.010		.064		.131
Excision
	Case number	53	46	36	70	49
Stromal TIL	Median	5%	5% (lower)	20%	5%	5%	5%
	IQR	2–50%	1–20%	1–50%	2–10%	2–50%	2–20%
	p-value		.077		.082		.293
CD8 positive TILs per high-power field *IQR – interquartile range

Follow-up data were available for 145 patients with 45 disease relapses and 29 died due to breast cancer-related causes. There were nine deaths due to other causes, among those three had disease relapses. The median follow-up time was 58 (8–194) months. Kaplan-Meier analysis showed significant association between high late post-surgery NLR and shorter DFS (p = .004), BCSS (p = .010) and OS (p = .004) (Fig. 3). No significant association with survival was found in the other two time points. In multivariate analysis, post-surgery NLR remains to be an independent predictor for OS (HR = 9.524, p < .001), BCSS (HR = 10.059, p = .001) and DFS (HR = 2.824, p = .016) (Table 3). Other consistent and independent predictors included post-chemotherapy ER status (p = .002 to .020) and nodal stage (ypN) (p = .001 to .012) (Table 3).

Table 3

Multivariate analysis of survival outcomes
	Hazard ratio	Lower 95% CI	Upper 95% CI	p-value
Overall survival
TIL (pre-chemotherapy/biopsy)	.954	.920	.990	.012
PR (pre-chemotherapy/biopsy)	.978	.961	.994	.009
ER (post-chemotherapy/excision)	.983	.969	.997	.020
Nodal stage (post-chemotherapy/excision, ypN)	1.991	1.247	3.179	.004
Late post-surgery NLR	9.524	2.920	31.063	.000
Breast cancer-specific survival	.944	.902	.988	.013
TIL (pre-chemotherapy/biopsy)	.977	.959	.996	.016
PR (pre-chemotherapy/biopsy)	.982	.965	.999	.034
ER (post-chemotherapy/excision)	2.058	1.203	3.521	.008
Nodal stage (post-chemotherapy/excision, ypN)	10.059	2.594	39.005	.001
Late post-surgery NLR	.982	.971	.992	.001
Disease free survival	.657	.479	.901	.009
ER (post-chemotherapy/excision)	1.924	1.267	2.922	.002
HER2 (post-chemotherapy/excision)	2.824	1.216	6.558	.016
Nodal stage (post-chemotherapy/excision, ypN)	.954	.920	.990	.012
Late post-surgery NLR	.978	.961	.994	.009
* CI – confidence interval, ER – estrogen receptor, HER2 – human epidermal growth factor receptor 2, NLR – neutrophil-lymphocyte ratio, PR – progesterone receptor

Using pre-chemotherapy NLR as a reference, cases with an increase in late post-surgery NLR of more than 0.5 showed significantly shorter DFS (p = .029) and BCSS (p = .018). Change in levels of post-chemotherapy NLR did not show statistically significant difference for outcomes, but subgroup analysis demonstrated that post-chemotherapy NLR-high cases with an increase of more than 0.5 from pre-chemotherapy NLR levels had better OS (p = .016) and BCSS (p = .047), with a similar trend for DFS (p = .095) (supplementary Fig. 1).

NLR is an established prognostic predictor in various human cancers (9). For breast cancer, a systematic review conducted by Corbeau et al. (10) revealed that the majority of studies showed negative prognostic correlation between all survival outcomes (DFS, BCSS and OS) and a high NLR (11–13), including in cohorts of patients receiving NAC (14, 15). TIL is a predictor of response to NAC (16), and a robust prognostic factor for both treatment-naive and post-neoadjuvant chemotherapy breast cancers (17–19), and is recognized as an important histologic feature for breast cancer classification in the latest World Health Organization classification of tumours of the breast (20). There is possible correlation between circulating (NLR) and local (TLR) immune microenvironment, supported by the strong association between high TIL and high circulating lymphocyte levels (i.e., low NLR) with favorable outcomes.

Findings from the current study reinforces the positive correlation between high TIL and low NLR in the neoadjuvant setting (Table 3). The cutoff for adopted high and low NLR was 2.6 in this study. In other cohorts of patients receiving NAC, cutoffs for NLR ranged from 1.7 to 3.3 (21, 22) but the majority were between 2.0 to 2.9 (14, 15, 23). Previous studies have reported inferior clinical outcomes for patients with high pre-chemotherapy (baseline) NLR (21, 22). In the current cohort, OS, BCSS and DFS for pre-chemotherapy NLR-high patients were all shorter but did not reach statistical significance (Table 1). Studies analyzing post-chemotherapy and late post-treatment NLR, have reported high-NLR after treatment to be indicative of shorter survival (24, 25). Kim et al. demonstrated association between an increase of NLR at one year post-surgery with poor prognosis (26). In line with the literature, all outcome metrics (OS, BCSS and DFS) were significantly worse in the NLR-high group for this cohort. An increase of NLR of more than 0.5 from pre-chemotherapy to late post-surgery was found to indicate worse DFS and BCSS, whereas for post-chemotherapy NLR-high cases, such an increase was associated with improved OS and BCSS (supplementary Fig. 1).

Evidence regarding the relationship between NLR and TILs is less established. Cohorts analyzing NLR and TIL in colorectal and ovarian cancer patients did not find correlations between NLR and TILs (4, 5, 8), whereas a negative correlation was demonstrated for biliary tract cancers (27). Regardless, all of those studies showed high-NLR and low-TIL to be associated with worse prognosis (4, 5, 8, 27). As for breast cancer, most studies on the relationship of NLR and TILs only included pre-treatment NLR (6, 7, 28, 29). Although high-NLR and low-TIL continue to demonstrate favorable prognosis (6, 7, 28, 29), correlation between NLR and TIL levels were not found (6, 7). One study by Lee et al. (30) which included pre-treatment and post-chemotherapy NLR reported that a decrease in NLR and same/increased TILs to be associated with prolonged DFS, but correlation analysis between NLR with TILs was not performed. An ongoing clinical trial aiming to evaluate NLR vs. TILs is currently underway (31). In the current study, TILs on H&E slides, similar to previous studies, was not associated with pre-treatment NLR, but demonstrated negative correlation to late post-surgery NLR. The addition of CD8 IHC showed that both stromal and tumor CD8 TIL levels were lower in pre-chemotherapy NLR-high cases (Table 2). These findings support a correlation between circulating and local lymphocyte levels in breast cancers.

High pre-chemotherapy NLR was associated with necrosis on biopsy and excision, whereas high post-chemotherapy NLR was associated with necrosis on excision (Table 1). TAMs were also more often seen in cases with high pre-chemotherapy NLR (Table 1). The positive association between NLR, tumor necrosis and TAMs has been reported in hepatopancreatic tumors (32, 33). But for breast cancers, literature search only yielded a smaller cohort which failed to demonstrate associations between NLR and tumor necrosis in breast cancer (34). It has been suggested that cancer-associated inflammatory cytokines, for example tumor necrosis factor alpha and colony stimulating factor contribute to the increase of neutrophil count (1, 35). High NLR reflects increased inflammatory activity attributable to cancer burden, proliferation and/or progression, which in turn is prognostically significant (1, 2). This postulation reconciles with the finding that a late increase in NLR is associated with poor outcomes (36). Interestingly, a further increase in NLR for cases with high NLR post-chemotherapy is indicative of longer survival. It is possible that a high post-chemotherapy NLR suggests residual disease, and further increases signifies an active and favorable immune response.

Multivariate analysis revealed that late-post surgery NLR was an independent negative predictive factor for OS, BCSS and DFS. Biomarker status and nodal staging were also consistently correlated with OS, BCSS and DFS. TIL showed independent correlation only for OS and BCSS but not DFS (Table 3). TIL, nodal status, hormone receptor markers and HER2 expression are recognized prognostic factors for breast cancer (37). With reference to available literature, biomarker status, tumor staging and grading, but not TILs, have been reported as independent prognostic factors to NLR (10, 14). Although NLR and TILs are correlated, there appears to be a certain degree of independency and separate mechanisms of interaction between the local (NLR) and circulating (TIL) immune microenvironment with breast cancer and its prognosis.

Most studies on populations receiving NAC compared pre-chemotherapy NLR only, and although negative correlation with survival were seen, multivariate analysis did not consistently demonstrate independent association (14, 15, 21, 38, 39). Two studies involving multiple time points reported significant association between 6-month and 24-to-36-month post-chemotherapy NLR with survival, but not pre-treatment NLR (24, 25). The current cohort echoes these two studies and suggests that post-chemotherapy NLR may be a stronger predictor of prognosis than pre-chemotherapy NLR. By analyzing multiple time points, it appears that a later NLR is more prognostically relevant. It may be possible that late high NLR levels signifies residual disease activity and recurrence (40).

By comparing NLR of multiple time points and TIL assessment using H&E and CD8 IHC, TILs were found to be negatively associated with late post-surgery NLR, and both tumoral and stromal CD8 + TILs were lower in pre-chemotherapy NLR-high cases. In addition, high NLR is also associated with the presence of tumor necrosis and TAMs for breast cancer. Multivariate analysis also demonstrated late post-surgery NLR to be independently associated with shorter OS, BCSS and DFS, over pre-chemotherapy and 3 months post-chemotherapy NLR. The association between NLR with tumor necrosis, TAM and TIL illustrate an interaction between the circulating and local tumor immune microenvironment. Late NLR appears to be a strong indicator of outcome and may be useful as a parameter for prognostication and disease monitoring.

Author contributions

JJXL – conceptualization, data curation, investigation, methodology, formal analysis, writing – original draft

SYBN – conceptualization, investigation, methodology, data curation

JYST – formal analysis, software, visualization, validation

VWYC – investigation

RKWH – resources, validation

JWHL – investigation

SWYN – investigation

LKS – data curation, investigation

YFT – investigation

GMT – conceptualization, methodology, validation, supervision, writing – review and editing

JJXL, SYBN and GMT conceptualized the study. JJXL, SYBN, JSY and GMT designed the study. JJXL, SYBN, VWYC, JWHL, SWYN, LKS and YFT collected data and performed investigations. JJXL and JYST analysed data and prepared figures. JYST, RKWH and GMT validated the findings. JJXL drafted the manuscript and GMT critically revised the manuscript. All authors have reviewed and approve of the final version of the manuscript.

Funding

This research was supported by the Government of the Hong Kong Special Administrative Region Health and Medical Research Fund (grant number 07180606).

Data availability statement

The data that support the findings of this study are available from the corresponding author, GT, upon reasonable request.

Ethical approval

This study was approved by the Joint Chinese University of Hong Kong - New Territories East Cluster clinical research ethics committee with waiver of requirement for written consent.

Conflicts of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

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No competing interests reported.

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Supplementary figure 1. Effects of change in neutrophil-lymphocyte ratio after neoadjuvant chemotherapy on survival

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Neutrophil-lymphocyte ratio reflects tumor infiltrating lymphocytes, tumor associated macrophages and independently predicts poor outcome in breast cancers with neoadjuvant chemotherapy

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